Myocardial Tissue Of Patients Research Articles

Abstract 18372: Clinical Threshold of Adenovirus Genome Load in Myocardial Tissues of Patients with Myocarditis and Dilated Cardiomyopathy

Background: Viral myocarditis is rarely recognized hence it is one of the most challenging diagnosis in cardiology. It leads to chronic dilated cardiomyopathy (DCM) and heart failure. Adenovirus is one of the most common cardiotropic viruses that cause viral myocarditis. However, the knowledge on AdV load in adenovirus associated myocarditis or DCM is unknown so far. Aim: To gain insight into the pathogenesis of AdV associated myocarditis, present study was aimed to determine AdV load in myocardial autopsy tissue of patients with myocarditis or DCM. Methods and Results: AdV load was determined using Taqman Real Time PCR in myocardial autopsy tissues obtained from 24 (11 male and 13 female) patients with histologically proven myocarditis or DCM whereas 12 noninflamed normal hearts obtained from autopsies served as controls. The AdV associated myocarditis was characterized by high mean viral load of 2034 genome equivalents (ge) per microgram of isolated nucleic acids in DCM patients with myocarditis as compared to viral load of 362 genome equivalents (ge) per microgram in normal hearts (p<0.005). Thus, from this data possibly AdV loads of more than 450 ge per microgram in myocardial autopsy are clinically relevant threshold for the maintenance of myocardial inflammation. Conclusion: The present study could derive the significant level of adenovirus load of 450 ge per microgram in myocardial tissues to be associated with adenovirus myocarditis and DCM. The knowledge on the clinical threshold of adenovirus load would help in diagnosing the clinically suspected viral myocarditis or DCM cases as well as would help in establishing an antiviral strategy to treat these patients.

Dynamic late gadolinium enhancement simply quantified using myocardium to lumen signal ratio: Normal range of ratio and diffuse abnormal enhancement of cardiac amyloidosis

To detect abnormal myocardial tissue in patients with diffuse myocardial disease, we propose a simple technique of late gadolinium enhancement (LGE) using routine myocardial imaging modalities. We retrospectively reviewed LGE images from 51 patients with normal myocardium and 10 patients with pathologically proven cardiac amyloidosis (CA). We obtained sequential LGE images from patients at 2, 5, 10, and 20 minutes after injection of Gd-DTPA (0.15 mmol/kg) with a fixed inversion time of 300 msec. We evaluated the signal intensity ratio of the myocardium to the left ventricular lumen (M/L) in one long and two short axial sections within 463 and 120 segments of normal myocardium and CA, respectively. Visually unenhanced and enhanced regions of myocardium were evaluated in each segment of patients with CA. Among normal myocardium, M/L (means ± standard deviation; SD) was stable with time (2, 5, 10, and 20 min: 0.34 ± 0.03, 0.31 ± 0.05, 0.34 ± 0.07, and 0.42 ± 0.11, respectively). The calculated M/L of unenhanced (0.60 ± 0.20, 0.68 ± 0.19, 0.76 ± 0.20, and 1.09 ± 0.25, respectively) and enhanced myocardium (0.77 ± 0.27, 0.99 ± 0.29, 1.20 ± 0.40, and 1.45 ± 0.54, respectively) in patients with CA was significantly greater than that seen for the normal myocardium at each time and increased over time. In patients with CA, diffuse myocardial abnormalities can be demonstrated using M/L, and this technique may be useful for the characterization of other myocardial diseases.

Ultrasonic Characterization (Integrated Backscatter) of Myocardial Tissue in Patients with Autosomal Dominant Polycystic Kidney Disease

Objective: To study changes in myocardial wall texture in autosomal dominant polycystic kidney disease (ADPKD) patients by ultrasonic integrated backscatter (IBS) analysis. Methods: Hypertensive and normotensive ADPKD patients, essential hypertension (EHP) patients and healthy volunteers were included in the study. All the subjects underwent conventional echocardiography and ultrasonic IBS of the myocardial wall. Both the calibrated IBS (C-IBS) and the systolic-diastolic cyclical variations in IBS (CV-IBS) were evaluated. Results: Mean C-IBS in hypertensive ADPKD patients was significantly higher than that in EHP patients and normotensive ADPKD patients. Mean C-IBS in normotensive ADPKD patients was significantly higher than that in healthy subjects. Mean CV-IBS in hypertensive ADPKD patients was significantly lower than that in EHP patients and normotensive ADPKD patients. Mean CV-IBS in normotensive ADPKD patients was significantly lower than that in healthy subjects. Multivariate analysis showed that the mean C-IBS was positively related to the systolic and diastolic blood pressure (SBP, DBP) and left ventricular mass index (LVMI); mean CV-IBS was positively correlated with contractile performance and transmitral E/A ratio and inversely correlated with SBP, DBP and LVMI. Conclusions: ADPKD patients experienced myocardial interstitial collagen deposition and impairment to myocardial contractile performance, which were both aggravated by hypertension. IBS seems to be a useful tool for the assessment of myocardial changes in ADPKD patients.

Detection and Quantification of Left Atrial Structural Remodeling With Delayed-Enhancement Magnetic Resonance Imaging in Patients With Atrial Fibrillation

Atrial fibrillation (AF) is associated with diffuse left atrial fibrosis and a reduction in endocardial voltage. These changes are indicators of AF severity and appear to be predictors of treatment outcome. In this study, we report the utility of delayed-enhancement magnetic resonance imaging (DE-MRI) in detecting abnormal atrial tissue before radiofrequency ablation and in predicting procedural outcome. Eighty-one patients presenting for pulmonary vein antrum isolation for treatment of AF underwent 3-dimensional DE-MRI of the left atrium before the ablation. Six healthy volunteers also were scanned. DE-MRI images were manually segmented to isolate the left atrium, and custom software was implemented to quantify the spatial extent of delayed enhancement, which was then compared with the regions of low voltage from electroanatomic maps from the pulmonary vein antrum isolation procedure. Patients were assessed for AF recurrence at least 6 months after pulmonary vein antrum isolation, with an average follow-up of 9.6+/-3.7 months (range, 6 to 19 months). On the basis of the extent of preablation enhancement, 43 patients were classified as having minimal enhancement (average enhancement, 8.0+/-4.2%), 30 as having moderate enhancement (21.3+/-5.8%), and 8 as having extensive enhancement (50.1+/-15.4%). The rate of AF recurrence was 6 patients (14.0%) with minimal enhancement, 13 (43.3%) with moderate enhancement, and 6 (75%) with extensive enhancement (P<0.001). DE-MRI provides a noninvasive means of assessing left atrial myocardial tissue in patients suffering from AF and might provide insight into the progress of the disease. Preablation DE-MRI holds promise for predicting responders to AF ablation and may provide a metric of overall disease progression.

Altered Interleukin-1 Receptor Antagonist and Interleukin-18 mRNA Expression in Myocardial Tissues of Patients with Dilatated Cardiomyopathy

Interleukin-1 (IL-1) is a potent regulator of cell proliferation, inflammation, and contraction of cardiovascular cells. It has been proposed that the IL-1/IL-1ra (IL-1 receptor antagonist) ratio influences these functions. Other members of the IL-1 family and the related caspase-1 also contribute to regulation of IL-1-mediated functions. We determined the mRNA expression of caspase-1, caspase-3, IL-1alpha , IL-1beta , IL-18, IL-1 receptor type I (IL-1-RI), and IL-1ra in left ventricle tissue of hearts from patients with ischemic or dilated cardiomyopathy (ICM or DCM) and in control tissues from unused donor transplant hearts in RT-PCR experiments. We show that the expression of caspase-1, caspase-3, IL-1beta , and IL-1-RI mRNA was not different between patients and control tissues. Furthermore, we did not find detectable amounts of IL-1alpha mRNA in any of these adult myocardial tissues. On the other hand, expression of IL-18 RNA was lower in myocardium of both patient groups compared with control hearts. Furthermore, IL-1ra mRNA expression was significantly lower in tissues of DCM patients compared with ICM patients and controls. This was in line with a trend towards lower IL-1ra protein levels in myocardial tissues of DCM patients. In contrast with the adult tissues discussed above, which did not express IL-1alpha mRNA, commercially available human fetal tissue expressed IL-1alpha mRNA. On the other hand IL-1beta mRNA was present in fetal and in adult human heart tissue. Our data provide evidence for an altered ratio of IL-1/IL-1ra in DCM patients. This dysregulation may contribute to pathogenesis and/or progression of heart disease by modulating the otherwise balanced IL-1-mediated functions in cardiovascular cells.

MRI Characterization of Myocardial Tissue in Patients with Fabry's Disease

Fabry's disease is a multisystem X-linked disorder of lysosomal metabolism frequently associated with left ventricular (LV) hypertrophy. In this study, we aimed to assess whether myocardial T2 relaxation time determined by a black blood multiecho multishot MRI sequence could be used to evaluate cardiac involvement in patients with Fabry's disease. Myocardial T2 relaxation time is prolonged in patients with Fabry's disease compared with that of hypertrophic patients and healthy control subjects. MRI may be useful for the characterization of myocardial tissue in patients with Fabry's disease.

Human Embryonic Stem Cell-Derived Cardiomyocytes: Inducing Strategies

Cell-based therapy is emerging as an innovative approach for the treatment of degenerative diseases, and stem cells appear to be an ideal source of cells for this. In cardiology, in particular, human embryonic stem cell (hESC)-derived cardiomyocytes theoretically fulfill most, if not all, of the properties of an ideal donor cell, but several critical obstacles need to be overcome. Many research projects are focusing on set-up strategies for directing hESC differentiation toward the cardiac lineage. It is one of the main difficulties in the search to provide a valuable source of cells to effect regeneration of myocardial tissue in patients with severe heart failure. To date, there are no easy and efficient protocols for the induction of hESC differentiation toward the cardiac lineage. Discovering new molecules or tools capable of doing this is imperative.

Adrenomedullin messenger RNA expression is increased in myocardial tissue of patients with idiopathic dilated cardiomyopathy

Increased plasma levels of adrenomedullin (ADM) have been reported in patients with congestive heart failure Immunohistochemical ADM has been identified in failing human ventricle, but the gene expression pattern of ADM messenger RNA (mRNA) in myocardial tissue of patients with heart failure has not been elucidated. In this study, gene expression of ADM mRNA (analyzed by northern blot) and tissue concentration of ADM (measured by radioimmunoassay) were assessed in the explanted hearts of 17 patients with idiopathic dilated cardiomyopathy (IDC) and in 7 organ donors with no cardiopathy (controls). Myocardial tissue samples of patients with IDC showed increased ADM mRNA gene expression ( p < 0.05) and decreased immunoreactive ADM protein content ( p < 0.02) compared with controls.

740 Sequential dobutamine stress echocardiography and TL-201 scintigraphy for the detection of viable myocardial tissue in patients with a previous myocardial infarction

740 Sequential dobutamine stress echocardiography and TL-201 scintigraphy for the detection of viable myocardial tissue in patients with a previous myocardial infarction

Effects of local injection of prilocaine-felypressin on the myocardial oxygen balance in dogs.

The authors investigated the effects of felypressin (Fely), a non-adrenergic vasoconstrictor, used together with prilocaine on myocardial oxygen balance. Six open-chest dogs were studied under urethane and alpha-chloralose anesthesia. Systolic arterial pressure, diastolic arterial pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure, heart rate, coronary blood flow (CBF), internal and external myocardial oxygen tension (int- or ext-PmO2), and cardiac output were observed. Three doses of Citanest-Octapressin, which contains 3% prilocaine and 0.03 IU ml(-1) Fely (Pri-Fely) - 0.09, 0.18, and 0.3 ml kg(-1)- were injected into the tongue. Observations were performed up to 60 min after the injection. The CBF and int-PmO2 was reduced following the injection of each of the three doses of Pri-Fely. There were negative correlations between the Pri-Fely dose per body weight and the maximum reductions in CBF (r = -0.52, P < 0.05), in int-PmO2 (r = -0.78, P < 0.05), and in ext-PmO2 (r = -0.55, P < 0.05), respectively [corrected]. These results suggest that an administration of Fely at doses more than 2.7-5.4 mIU kg(-1) (3-6 cartridges of Pri-Fely) may induce an imbalance between the oxygen supply and demand in myocardial tissues of patients with cardiovascular diseases.

123I]-phenylpentadecanoic acid uptake in patients with dilated cardiomyopathy.

The rate constant for global fatty acid influx (k(1)) was studied in 12 male patients with dilated cardiomyopathy (DCM). 10 normal subjects served as controls. 201-Thallium (201TI) and [123I]-phenyl-pentadecanoic acid (IPPA) were administered during bicycle exercise under fasting conditions. All patients showed non-homogeneous tracer uptake defects for 201TI and IPPA. k(1) was significantly higher in DCM patients than controls. k(1) showed significant inverse correlation between cardiac index, left-ventricular ejection fraction, left-ventricular enddiastolic pressure and echocardiographic left-ventricular ejection fraction. We presume that an increased regional rate constant of IPPA influx into the myocardial tissue in patients with DCM reflects a compensatory mechanism of altered myocardium.

Expression of tumor necrosis factor ligand superfamily costimulatory molecules CD27L, CD30L, OX40L and 4-1BBL in the heart of patients with acute myocarditis and dilated cardiomyopathy

Background: T-cell-mediated myocardial damage is known to be involved in acute myocarditis and dilated cardiomyopathy. Recently, we found that tumor necrosis factor (TNF) ligand superfamily costimulatory molecules, especially 4-1BBL, played an important role in the myocardial damage of murine acute viral myocarditis. Methods and results: To investigate the roles for CD27L, CD30L, OX40L and 4-1BBL, which belong to TNF ligand superfamily, in the development of acute myocarditis and dilated cardiomyopathy, we analyzed the expression of these antigens in the myocardial tissues of patients with acute myocarditis and dilated cardiomyopathy. We also examined expression of the receptors for these molecules, CD27, CD30, OX40 and 4-1BB, which belong to TNF receptor superfamily, on the infiltrating cells. Strong expression of CD27L, CD30L and 4-1BBL and weak to moderate expression of OX40L was found in the cardiac myocytes of patients with acute myocarditis. Moderate expression of CD27L, CD30L and 4-1BBL and weak expression of OX40L was found on the cardiac myocytes of patients with dilated cardiomyopathy. Most of the infiltrating cells expressed CD27, CD30 and 4-1BB and a part of the infiltrating cells expressed OX40. Conclusions: Our findings suggest that expression of TNF ligand superfamily costimulatory molecules on cardiac myocytes may play a role in the cell-mediated myocardial damage in patients with acute myocarditis and dilated cardiomyopathy as in murine viral myocarditis.

Nitric oxide synthase II mRNA expression in cardiac tissue of patients with heart failure undergoing cardiac transplantation

Objectives: To examine whether inducible nitric oxide synthase is expressed in myocardial tissue of patients with heart failure. Background There is increasing evidence that alterations in nitric oxide synthesis are of pathophysiologic importance in heart failure. Nitric oxide (NO) can exert negative inotropic and cytotoxic effects on cardiomyocytes. A number of studies have shown altered nitric oxide production by the endothelial constitutive isoform of nitric oxide synthase (NOS III), but there is little information on the role of NOS II. Expression of NOS II could lead to excessive production of NO in the myocardium and affect cardiac contractility. Methods NOS II mRNA expression in myocardial tissue of 18 patients with idiopathic dilated cardiomyopathy (DCM), 7 patients with ischemic cardiopathy and severe ventricular dysfunction (ISCH), 4 patients with acute myocardial infarction (AMI) and 11 controls. Serum concentration of NO 2 −/NO 3 − (NOx) was also measured. Results NOS II gene expression occurred in all the patients with DCM, in 1 out of the 7 ISCH patients, in 2 out of the 4 patients with AMI and in none of the controls. Moreover, DCM patients showed a significant 6-fold increase in NOx concentration (253 ± 47 nm/ml) as compared to controls (40 ± 2 nm/ml) P < 0.001, a phenomenon not observed in ISCH patients (56 ± 3 nm/ml). Conclusions NOS II expression occurs in failing human cardiac myocytes and can play an specific role in the pathogenesis of DCM.

Expression of costimulatory molecules B7-1, B7-2, and CD40 in the heart of patients with acute myocarditis and dilated cardiomyopathy.

In patients with acute myocarditis and dilated cardiomyopathy (DCM), we previously reported that antigen-specific T cells infiltrate the heart and play an important role in the myocardial damage involved. For antigen-specific T-cell activation to occur, it is necessary for T cells to receive a costimulatory signal provided by costimulatory molecules expressed on antigen-presenting cells (APCs) as well as the main signal provided by binding of T-cell receptors to the antigen. To investigate the roles of the costimulatory molecules B7-1, B7-2, and CD40 in the development of acute myocarditis and DCM, we analyzed the expression of these antigens in the myocardial tissues of patients with acute myocarditis and DCM. We also examined the expression of a cytolytic factor, perforin, in the infiltrating cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, because both killer lymphocytes are thought to damage B7-1-expressing APCs. We found that B7-1, B7-2, and CD40 were moderately to strongly expressed in the cardiac myocytes of patients with acute myocarditis. Weak to moderate expression of these antigens was also found in the cardiac myocytes of patients with DCM. There was infiltration of perforin-expressing CTLs and NK cells in the myocardial tissues of patients with acute myocarditis and DCM. Our findings strongly suggest that expression of B7-1, B7-2, and CD40 antigens on cardiac myocytes may make them APCs for CTLs and NK cells and that they may play an important role in the direct myocardial damage by these killer cells in acute myocarditis and DCM.

Characterization of myocardial tissue in patients undergoing maintenance hemodialysis by quantitative echocardiography

The uremic state affects myocardial structure, bringing about, among other things, interstitial calcium deposition. Abnormalities of myocardial structure can be assessed quantitatively and noninvasively during life by the analysis of the gray-level distribution of conventional two-dimensional echocardiograms. The aim of this study was to evaluate the role of quantitative echocardiography in providing information on myocardial structure in patients under maintenance hemodialysis and to relate the ultrasonic findings with abnormalities in calcium-phosphate metabolism. Forty patients undergoing dialysis without abnormalities in left ventricular regional and global function and 17 hypertensive patients with comparable left ventricular hypertrophy were studied. The distribution of the gray levels within a region of interest in the interventricular septum was analyzed off-line by an array processor-based computer. Compared with hypertensive patients, patients undergoing dialysis showed a greater myocardial echogenicity (mean 92 ± 20 versus 72 ± 15; p = 0.004) and a reduced homogeneity of distribution of gray levels (entropy 4.5 ± 0.2 versus 4.2 ± 0.2, p < 0.01; uniformity 0.010 ± 0.003 versus 0.020 ± 0.004, p < 0.005). In the same patients, a significant negative linear relation was found between entropy and calcium-phosphate product ( r = −0.66; p = 0.001). Quantitative analysis of conventional two-dimensional echocardiograms allows the detection of a pathologic myocardial structure in patients under maintenance hemodialysis with normal left ventricular function. These abnormalities are related to disorders of calcium-phosphate metabolism and bear no relationship to the degree of left ventricular hypertrophy.

急性心筋梗塞における誘導型一酸化窒素合成酵素（ｉＮＯＳ）の心筋組織での発現の意義

To investigate whether the nitric oxide (NO) is involved in the myocardial damage in acute myocardial infarction (AMI), ventricular myocardial tissue of autopsied cases with myocardial infarction was examined by immunohistochemical staining with anti-inducible NO synthase (iNOS) and anti-nitrotyrosine antibody.The damaged residual myocardium were positively stained with anti-iNOS antibody and anti -nitrotyrosine antibody in AMI. These findings were not obtained in the myocardial tissue of patients who died shortly in the early stage when myocardial cells reveal contraction band necrosis with minimal inflammatory cell infiltration. And also they were not obtained in patients with old myocardial infarction.Since iNOS development accompanied by cell infiltration was noted in the damaged myocardium and nitrotyrosine was also disclosed in the same area, it is suggested that not only NO but also peroxynitrite is involved in myocardial damage in AMI.

Cardiac-derived neutrophil chemotactic factors: Detection in coronary sinus effluents of patients undergoing myocardial revascularization

Recent studies from our laboratory have demonstrated the release of neutrophil chemotactic factors from isolated rabbit hearts perfused with cardioplegic solutions and from ischemic dog hearts after coronary artery occlusion for 1 hour. On the basis of these animal studies, a test is now made of the hypothesis that neutrophil chemotactic factors are released by myocardial tissues of patients who undergo surgical myocardial revascularization. By means of modified Boyden chambers, the levels of neutrophil chemotactic factors were measured in effluent collected from the coronary sinuses of six patients undergoing cardiopulmonary bypass during periods of cold cardioplegia. Plain cardioplegic solutions were also analyzed. The standard formyl-methionyl-leucyl-phenylalanine, a stimulant of neutrophil recruitment, was used as a positive control solution. Results indicated the recovery of significantly high levels of neutrophil chemotactic factors in patient samples (i.e., 128% +/- 19% of formyl-methionyl-leucyl-phenylalanine) compared with control plain cardioplegic solution (less than 5% of formyl-methionyl-leucyl-phenylalanine) (p less than 0.0001). A standard checkerboard analysis indicated that the observed activity is chemotactic (i.e., directed migration) and not chemokinetic (i.e., random migration). This study also showed that these factors are proteins of a molecular weight in excess of 300 kd and exhibit in vivo activity by recruiting neutrophils into rabbit skin. The absence of immune cell-derived chemoattractants such as interleukin-1 and leukotriene B4 in these coronary sinus effluents suggests that the observed chemotactic activity is cardiac derived. Results of this investigation therefore demonstrate the release of neutrophil chemotactic factors by ischemic human hearts during cardiopulmonary bypass.

The poorly controlled hypertensive patient

S YSTOLIC AND DIASTOLIC hypertension are important indicators of cardiovascular disease. Borderline hypertension is usually defined as a blood pressure between 160/ 100 and 140/90 mm Hg. In essential hypertension, arterial pressure increases, as does systemic vascular resistance, which produces a pressure overload on the left ventricle and results in concentric ventricular hypertrophy. Patients with hypertension and ventricular hypertrophy are at increased risk for sudden death, ventricular dysrhythmias, heart failure, and myocardial ischemia. Ventricular hypertrophy increases myocardial oxygen demand while decreasing myocardial oxygen supply to the hypertrophied myocardium. Patients with hypertension should be assumed to have coronary artery disease until proven otherwise. Ventricular dysrhythmias occur due to myocardial ischemia, pressure overload, and fibrotic myocardial tissue in patients with ventricular hypertrophy. The end stage of hypertensive cardiovascular disease is left ventricular failure. Therefore, the margin of safety is greatly reduced in the hypertensive patient.

Myocardial carnitine in end-stage congestive heart failure

To test the hypothesis that carnitine is decreased in the myocardial tissue of patients with end-stage congestive heart failure (CHF), left ventricular myocardial carnitine was measured in 51 patients undergoing orthotopic cardiac transplantation. The study group included patients with idiopathic dilated cardiomyopathy, coronary artery disease, myocarditis and rheumatic heart disease. Myocardial carnitine varied in different cardiac chambers. In normal control hearts, the left and right ventricular total carnitine was similar, but the ventricles had higher levels than the atria (p < 0.005); in 30 hearts in CHF, the left ventricular total carnitine was higher than in the right ventricle (p < 0.001) and both ventricles had higher total carnitine than the atria (p < 0.005). Only 7 of 51 patients with CHF had low myocardial carnitine, whereas plasma carnitine was elevated in all diagnostic groups of end-stage CHF studied.